TAR DNA-binding protein 43 (TDP-43) is an hnRNP-like RNA binding protein implicated in a large number of cellular functions. These functions include repression of HIV transcription, regulation of alternative RNA splicing, control of mRNA stability, and mRNA biogenesis. See, e.g., Sephton et al, 2011, J. Biol. Chem. 286, 1204-1215; Tollervey et al., 2011, Nat. Neurosci. 14, 452-458; Polymenidou et al., 2011, Nat. Neurosci. 14, 459-468; Buratti et al., 2012, RNA Biol. 7, 420-429; Xiao et al, 2011, Mol. Cell. Neurosci. 47, 167-180.
TDP-43 is also implicated in pathological processes. Accumulation of TDP-43 containing cytoplasmic inclusions is a shared hallmark in a broad spectrum of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer disease (AD). See, e.g., Cohen et al., 2011, Trends Mol. Med. 17, 659-667; Buratti et al., 2012, RNA Biol. 7, 420-429; Sendtner et al., 2011, Nat. Neurosci. 14, 403-405]. The mechanisms that link TDP-43 to neurodegeneration, however, are unclear, and there is a need for specific and improved methods for treating, profiling, and identifying neurodegenerative disorders associated with TDP-43.
The instant application meets these and other needs in the art, partly by developing and applying new methods to profile the transposable element (TE) transcriptome. These profiling studies unexpectedly show that TDP-43 broadly targets TEs, and that TEs are widely over-expressed in animal models of TDP-43-associated neurodegenerative disorders, as well as in patients with frontotemporal lobar degeneration (FTLD).